The long-range objective is to develop a clinically useful primate model for endometriosis-associated infertility in order to define underlying molecular biological and physiologic mechanisms and to test the efficacy of experimental medical treatments. Our preliminary results are indicative that the aberrant expression of aromatase and cyclo-oxygenase (COX)-2 and the deficiency of 17beta-hydroxysteroid dehydrogenase type 2 (17beta-HSD-2) in endometriosis (in comparison with the eutopic endometrium) give rise to elevated local levels of estradiol, which is mitogenic for endometriotic tissue. These findings are clinically relevant, because treatment of a postinenopausal woman with an unusually-long- standing and severe case of recurrent endometriosis using an aromatase inhibitor nearly eradicated the disease. We hypothesize that excessive estrogen formation in endometriosis represents an important abnormality associated with infertility and a potential target in its treatment. Additionally, the deficiency of the progesterone-induced enzyme 17beta- HSD-2 in endometriotic tissue and severely altered ratio of progesterone receptor isoforms represent, in part, the molecular basis of a general progesterone resistance in endometriosis, which is also confirmed clinically by resistance of this disease to treatment with progestins. Results of our preliminary findings, however, can only be interpreted with caution, since the models used were either human endometriotic cell cultures or mice with transplanted uterine tissues. Baboon is an appropriate model, since these animals develop endometriosis spontaneously similar to the human disease and can be manipulated surgically and hormonally to answer fundamental questions. Consequently, we obtained institutional bridge funds for a year to perform a limited study on 6 baboons. The following studies, however, require much larger numbers of baboons. These can be performed extremely efficiently in the Institute for Primate Research in Nairobi, given the size of the colony and the level of enthusiasm and expertise in baboon endometriosis in this institution. The first specific aim of this application is to characterize the molecular and cellular mechanisms responsible for excessive estrogen formation and progesterone resistance in a baboon endometriosis model. Endometriosis will be induced by injection of menstrual material into the pelvic cavity. Alternatively, baboons that develop endometriosis spontaneously will be identified by laparoscopy. Activities of aberrant or deficient enzymes in endometriotic lesions will be determined using in vivo conversion assays. We will then determine the expression of aromatase, COX-2, 17beta-HSD- 2 and steroid receptor isoforms in endometriotic tissue biopsies. Finally, end results such as proliferation and apoptotic cell death in baboon endometriotic lesions will be determined in response to various hormonal treatments including aromatase inhibitors. The second specific aim is to determine the mechanism of infertility associated with endometriosis and the effectiveness of early medical treatment for prevention. Baboons with or without endometriosis will be monitored for ovulation. Possible defects in fertilization, implantation and early miscarriage will be detected. Once major mechanisms are characterized, we will determine whether infertility associated with endometriosis can be prevented or treated medically using novel strategies.